Obesity is an epidemic problem in the United States and is among the most important health challenges of the 21st Century. The major consequences of obesity are increased rates of mortality and morbidity from heart disease, hypertension, diabetes, sleep-disordered breathing, and the metabolic syndrome. Many obese adults experience exertional dyspnea and are unable to exercise. Therefore, exertional dyspnea in obese adults is not only an important and prolific clinical concern it is an obstacle to the prevention and treatment of obesity and obesity-related comorbidities. Although most obese adults with dyspnea on exertion are generally considered to be deconditioned, our preliminary data challenge this conventional wisdom. For example, in women with dyspnea on exertion, we have found the oxygen cost of breathing (i.e., work of breathing) to be markedly increased and highly associated with exertional dyspnea. Thus, it is presently unclear if exertional dyspnea in obesity is due to cardiovascular deconditioning, in which exercise training would be dramatically beneficial, or to obesity-related changes in respiratory mechanics, in which aggressive weight loss measures may be necessary before exercise training can be tolerated. The overall objective of this application is to investigate whether exertional dyspnea in otherwise healthy obese adults can be ameliorated by endurance exercise training (i.e., increase in cardiovascular conditioning), or by weight loss (i.e., decrease in obesity related-respiratory limitations, specifically, the oxygen cost of breathing). We hypothesize that exertional dyspnea in otherwise healthy obese adults will not improve with endurance exercise training since obese adults with exertional dyspnea are not deconditioned, and exercise training alone is unlikely to decrease obesity-related respiratory limitations, specifically the oxygen cost of breathing. In contrast, we hypothesize that exertional dyspnea will be ameliorated with weight loss, since weight loss should decrease obesity related-respiratory limitations, in particular, the oxygen cost of breathing. In this application, we will utilize two interventions to investigate our proposals: 1) endurance exercise training without weight loss, and 2) weight loss without endurance exercise training. Specific Aims: To accomplish the overall objective, the following hypotheses will be tested: 1) Endurance exercise training will not ameliorate exertional dyspnea in obese adults with dyspnea on exertion;and 2) Weight loss, especially loss of chest wall fat, will ameliorate exertional dyspnea in obese adults with dyspnea on exertion. Our long-term objective is to investigate the mechanism of exertional dyspnea in obese adults and provide novel and clinically relevant results that could potentially alter interventional approaches for preventing obesity, treating obesity, and reducing the risk of heart disease, hypertension, and the metabolic syndrome in obese patients. PUBLIC HEALTH RELEVANCE: Dyspnea (shortness of breath) on exertion in obese adults is a common health problem in America. The cause is currently unknown, and in many instances exertional dyspnea is an obstacle to the prevention and treatment of obesity and coexisting diseases. Our research will investigate the mechanisms of this discomfort and the effectiveness of exercise training and weight loss in reducing dyspnea on exertion. The results of this research could potentially alter interventional approaches for preventing obesity, treating obesity, and reducing the risk of heart disease in obese patients. Thus, these results will have broad and immediate clinical relevance to the treatment of obesity and obesity-related comorbidities.